The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to describe or constitute prior art to the invention.
Kit signaling is critical for fetal gonadal development, and continues to play a role in adult fertility (Mauduit et al. (1999) Human Reproduction Update 5:535–545). Spermatogenesis is inhibited in the absence of SCF (Ohta et al. (2000) Development 127:2125–2131) or the ability of Kit to signal through the PI3 kinase pathway (Blume-Jensen et al. (2000) Nature Genetics 24:157–162; Kissel et al. (2000) EMBO Journal 19:1312–1326). Kit expression has also been observed to be lower in sub-fertile testes than in normal testicular tissue (Feng et al. (1999) Fertility & Sterility 71:85–89). Kit signaling is also important for oogenesis and folliculogenesis (Parrott & Skinner (1999) Endocrinology 140:4262–4271; Driancourt et al. (2000) Reviews of Reproduction 5:143–152). These observations suggest that Kit kinase inhibitors would reduce both male and female fertility.
As a key mediator of mast cell function, Kit may play a role in pathologies associated with mast cells. For example, mast cells have been associated with interstitial fibrosis in chronic rejection of human renal allografts (Pardo et al. (2000) Virchows Archiv 437:167–172). Mast cells have also been implicated in liver allograft rejection (Yamaguchi et al. (1999) Hepatology 29:133–139) and in liver fibrosis, where hepatic stellate cells produce the SCF that recruits the mast cells (Gaca et al. (1999) J. Hepatology 30:850–858). These observations suggest the Kit kinase inhibitors may help prevent organ rejection and fibrosis.
Mast cells have also been implicated in the pathology of multiple sclerosis (Secor et al. (2000) J. Experimental Medicine 191:813–822) and ischemia-reperfusion injury (Andoh et al. (1999) Clinical & Experimental Immunology 116:90–93) in experimental models using mice with mutant Kit receptors that are deficient in mast cells. In both cases, the pathology of the disease was significantly attenuated relative to mice with normal Kit and mast cells populations. Thus, the role of mast cells in these diseases suggests that Kit kinase inhibitors might be useful therapeutics.
Cellular signal transduction is a fundamental mechanism whereby extracellular stimuli are relayed to the interior of cells and subsequently regulate diverse cellular processes. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of proteins. Phosphorylation of polypeptides regulates the activity of mature proteins by altering their structure and function. Phosphate most often resides on the hydroxyl moiety (—OH) of serine, threonine, or tyrosine amino acids in proteins.
Enzymes that mediate phosphorylation of cellular effectors generally fall into two classes. The first class consists of protein kinases which transfer a phosphate moiety from adenosine triphosphate to protein substrates. The second class consists of protein phosphatases which hydrolyze phosphate moieties from phosphoryl protein substrates. The converse functions of protein kinases and protein phosphatases balance and regulate the flow of signals in signal transduction processes.
Protein kinases and protein phosphatases are generally divided into two groups: receptor and non-receptor type proteins. Most receptor-type protein tyrosine phosphatases contain two conserved catalytic domains, each of which encompasses a segment of 240 amino acid residues. Saito, et al., 1991, Cell Growth and Diff 2:59–65. Receptor protein tyrosine phosphatases can be subclassified further based upon the amino acid sequence diversity of their extracellular domains. Saito, et al., supra; Krueger, et al., 1992, Proc. Natl. Acad. Sci. USA 89:7417–7421.
Protein kinases and protein phosphatases are also typically divided into three classes based upon the amino acids they act upon. Some catalyze the addition or hydrolysis of phosphate on serine or threonine only, some catalyze the addition or hydrolysis of phosphate on tyrosine only, and some catalyze the addition or hydrolysis of phosphate on serine, threonine, and tyrosine.
Tyrosine kinases can regulate the catalytic activity of other protein kinases involved in cell proliferation. Protein kinases with inappropriate activity are also involved in some types of cancer. Abnormally elevated levels of cell proliferation are associated with receptor and non-receptor protein kinases with unregulated activity.
In addition to their role in cellular proliferation, protein kinases are thought to be involved in cellular differentiation processes. Cell differentiation occurs in some cells upon nerve growth factor (NGF) or epidermal growth factor (EGF) stimulation. Cellular differentiation is characterized by rapid membrane ruffling, cell flattening, and increases in cell adhesion. (Chao, 1992, Cell 68:995–997).
In an effort to discover novel treatments for cancer and other diseases, biomedical researchers and chemists have designed, synthesized, and tested molecules that inhibit the function of protein kinases. Some small organic molecules form a class of compounds that modulate the function of protein kinases. Examples of molecules that have been reported to inhibit the function of protein kinases are bis-monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642), vinylene-azaindole derivatives (PCT WO 94/14808), 1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992), styryl compounds (by Levitzki, et al., U.S. Pat. No. 5,217,999, and entitled “Styryl Compounds which Inhibit EGF Receptor Protein Tyrosine Kinase, styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 A1), seleoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660), and benzylphosphonic acid compounds (PCT WO 91/15495).
The compounds that can traverse cell membranes and are resistant to acid hydrolysis are potentially advantageous therapeutics as they can become highly bioavailable after being administered orally to patients. However, many of these protein kinase inhibitors only weakly inhibit the function of protein kinases. In addition, many inhibit a variety of protein kinases and will therefore cause multiple side-effects as therapeutics for diseases.
Despite the significant progress that has been made in developing compounds for the treatment of cancer, there remains a need in the art to identify the particular structures and substitution patterns that form the compounds capable of modulating the function of particular protein kinases.